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After a long period of failure in development, two new medications (phentermine/topiramate ER - Qsymia™ and lorcaserin - Belviq®) have been approved by the US Food and Drug Administration for long-term weight management in persons with obesity (BMI ≥ 30 kg/m(2)) or in overweight persons (BMI ≥ 27 kg/m(2)) with comorbidities. Another medication, bupropion/naltrexone, is undertaking a cardiovascular outcomes trial and an analysis in 2014 will determine its approval and release. The most widely prescribed drug for obesity, phentermine, used since 1959 for short-term weight management, has been released in a new formulation. This paper reviews these new medications, and other important events in the landscape for management of obesity, with an eye to the interests of physicians who manage hypertension. All the new drugs under discussion are re-fittings of old agents or fresh approaches to old targets; thus, what is old is new again in the pharmacotherapy of obesity.

Background: Early weight loss is generally considered to predict long-term weight outcome in obese patients, and this is reflected in prescribing guidelines for antiobesity drugs. For example, the current prescribing guidelines for the antiobesity drug, sibutramine, indicate that if patients have not lost 2 kg (or 4 lb) in the first 4 weeks of treatment with sibutramine 10 mg, the physician should re-evaluate the therapy, which may result in increasing the dose to 15 mg or discontinuation. This regimen may deny treatment to a large group of patients who might otherwise benefit, particularly patients with type 2 diabetes who often find it more difficult to lose weight than non-diabetic obese individuals., Materials: We have re-analysed pooled data from seven randomized, controlled studies of sibutramine-induced weight loss and maintenance in which patients (n = 928; 75% female) had taken sibutramine 10 or 15 mg continuously for 12 months, in order to determine the predictors of success in weight loss (defined as loss of at least 5% of initial body weight at Month 12) in both diabetic and non-diabetic patients. Sensitivity and specificity analyses were used to calculate optimal predictive values., Results: In both diabetic and non-diabetic patients, weight loss of 4 kg at 3 months was identified as the optimal predictor for achieving at least 5% weight loss at 12 months. This target was associated with the best average values for sensitivity, specificity and accuracy, as well as high positive (78% vs. 84% for non-diabetics and 76% vs. 85% for diabetics, compared to existing guidelines target of 2 kg after 1 month treatment) and negative predictive values (63% vs. 71% for non-diabetics; 52% vs. 70% for diabetics)., Conclusion: Sibutramine, in conjunction with diet and exercise, should be continued for at least 3 months (providing there are no adverse effects) to determine whether or not patients are likely to achieve a clinically valid outcome at 1 year. This highlights the need to ensure that regulatory restrictions reflect the needs of clinical practice.

Drugs that act through noradrenergic and serotonergic mechanisms have historically served as the mainstays of pharmacologic treatments for obesity. This review addresses the following three topics: a brief discussion of older weight loss medications approved for short-term use (benzphetamine, phendimetrazine, diethylpropion, mazindol, and phentermine), as well as over-the-counter adrenergic drugs (phenylpropanolamine and ephedrine); recent clinical studies documenting the safety and efficacy of a new medication for obesity treatment, sibutramine, recently approved by the Food and Drug Administration for long-term use; and recent studies characterizing the valvulopathy associated with fenfluramine and dexfenfluramine, serotonergic medications for obesity which have been removed from the markets.

Objective: To evaluate, in compliant patients, the pharmaceutical costs of treating obesity with fenfluramine/mazindol, fenfluramine/phentermine, caffeine/ephedrine, or mazindol relative to the pharmaceutical costs of treating obesity-related comorbid conditions and reducing cardiovascular risk., Methods and Procedures: Subjects were between 18 and 60 years of age with a BMI of >30 kg/m2. Pharmaceutical costs were evaluated in 73 of 220 subjects taking medications for diabetes, hyperlipidemia, or hypertension before and after treatment using fenfluramine with mazindol or phentermine. The pharmaceutical cost of weight loss, cardiac risk reduction, and low-density lipoprotein (LDL) cholesterol reduction was calculated for fenfluramine with mazindol or phentermine, caffeine with ephedrine, or mazindol alone, and compared to approved lipid-lowering medications., Results: Losses of 6% to 10% of initial body weight reduced pharmacy costs $122.64/month for insulin treated diabetes, $42.92/month for sulfonylurea-treated diabetes, $61.07/month for hyperlipidemia treated with medication, and $0.20/month for hypertension treated with medication. Blood pressure and laboratory evidence of insulin resistance improved in all medication groups. Caffeine/ephedrine was most cost-effective of the three treatments in reducing weight, cardiac risk, and LDL cholesterol., Discussion: Obesity medications produced a substantial weight loss in compliant patients and resulted in a net pharmaceutical cost savings compared to treating obesity related comorbid conditions.

Objective: The prevalence of cardiac valvular regurgitation demonstrated by echocardiography in patients who took appetite-suppressant medication for weight loss has been assessed at 5%-30%. We studied 86 patients who had echocardiograms before treatment with appetite suppressants to determine the incidence of new cases and to evaluate the clinical implication of the echocardiographic findings., Research Methods and Procedures: We studied 69 men [Mean+/-Standard Deviation (S) age 49+/-8] and 17 women (mean+/-S age 50+/-7) who had 233 echocardiograms before, during, and after a weight-loss program that used predominantly fenfluramine (or dexfenfluramine) with mazindol (or phentermine). Mean drug exposure was 17 months. Blinded echocardiographic readings were performed to identify and grade aortic regurgitation (AR) or mitral regurgitation (MR)., Results: Seven of 86 patients (8%) had pre-existing regurgitation with five (6%) meeting our case definition. Thirteen (16.5%) of initially normal patients developed valvular regurgitation and were new cases. Of the new cases, 12 were grade I/IV AR and one was both grade II/III MR and II/IV AR. All 13 patients were asymptomatic, and only two aortic insufficiency murmurs could be auscultated. There was significantly greater risk for developing valvulopathy for those who took medications longer than 6 months (p = 0.03), and no new cases were observed in patients exposed for less than 8 months. No increased risk associated with age, presence of hypertension, or exposure to fenfluramine-phentermine combination was demonstrated. Although there was a higher incidence of new regurgitation in women (31% vs. 13% for men), this was not statistically significant (p = 0.093)., Discussion: Some patients who had normal echocardiograms at baseline developed cardiac valvular regurgitation after exposure to fenfluramine or dexfenfluramine with mazindol or phentermine. The development of valvulopathy was significantly correlated with duration of exposure. The clinical implications of echocardiographically demonstrated regurgitation are uncertain, since there were only two audible murmurs and no other clinically relevant signs or symptoms among the patients.

Objective: Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity., Research Methods and Procedures: Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes., Results: Weight loss was dose-related and statistically significant vs. placebo (p<0.05) across all time-points for a 5 mg/day to 30 mg/day dosage of sibutramine. At week 24, percent weight loss from baseline for completers was: placebo, 1.2%; 1 mg, 2.7%; 5 mg, 3.9%; 10 mg, 6.1%; 15 mg, 7.4%; 20 mg, 8.8%; and 30 mg, 9.4%. Weight loss achieved at week 4 was predictive of weight loss achieved at week 24. Patients losing weight demonstrated an increase in serum high density lipoprotein cholesterol and reductions in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, and uric acid. Small mean increases in blood pressure and pulse rate (with considerable individual variability) were observed in patients treated with sibutramine. The most frequent adverse events were dry mouth, anorexia, and insomnia., Discussion: Sibutramine administered once daily for 24 weeks in the weight loss phase of treatment for uncomplicated obesity produced dose-related weight loss and was well tolerated. Improvements in serum lipids and uric acid accompany sibutramine-induced weight loss. Most of the adverse events observed on sibutramine are related to its pharmacology, including small mean increases in blood pressure and heart rate.

The acceptance of medication as a legitimate adjunct to diet and behavior modification in the treatment for obesity is an emerging phenomenon spurred by advances in understanding the biologic basis of body weight regulation and by the demonstration of safe and effective chronic maintenance of weight loss using a pharmacobehavioral approach. The decision to medicate for obesity depends on good clinical judgment based on such considerations as body mass index; body composition; body fat dissociation; age; sex; and comorbid conditions, such as diabetes and hypertension. Several nonadrenergic agents and a serotonergic agent have FDA-approved indications for weight loss. Phenylpropanolamine is available over the counter. Clinical trials support the efficacy of fluoxetine and ephedrine or caffeine in producing weight loss, although these agents do not have FDA-approved indications for treatment for obesity. In addition, new agents are being developed or are anticipated for approval. The use of existing agents in combination and their use adjunctive to diet and behavioral approaches to obesity treatment are fertile areas for research. The expectant attention to this subject is demanded by the imperative that the health in one three people in the United States is adversely affected by obesity.

Sibutramine is a novel new pharmacologic agent which is a specific reuptake inhibitor for norepinephrine and serotonin. Preclinical data show that sibutramine and its two metabolites reduce food intake of animals eating either high or low carbohydrate diets and of obese Zucker rats. An 8-week clinical trial showed a dose-dependent decrease on body weight. Sibutramine, 5 and 20 mg/day, produced a dose-related weight loss in obese subjects compared to placebo in an 8-week trial. In doses varying from 1 to 30 mg, sibutramine also produced a dose-dependent decrease in weight in the healthy obese population when used in 6-,8-,12-24- and 52-week trials. Although the majority of the weight loss occurred during the first 12 weeks of treatment, weight loss had not plateaued in by 24 weeks in the higher doses. Side effects were mild. This drug shows promise as an antiobesity drug.